1-benzylpyrazole-3-carboxylic acid tricyclic derivatives as cannabinoid receptor antagonists

ABSTRACT

Tricyclic derivatives of 1-benzylpyrazole-3-carboxylic acid which are antagonists of the cannabinoid CB 2  receptors; their method of preparation and pharmaceutical compositions containing them.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a 35 U.S.C. §371 application of PCT InternationalApplication No. PCT/FR00/03047 filed Nov. 2, 2000, which in turn claimspriority from French Application No. 99/13847, filed Nov. 3, 1999.

The subject of the present invention is compounds which are antagonistsof the cannabinoid CB₂ receptors, their preparation, pharmaceuticalcompositions containing them. The compounds of the invention aretricyclic derivatives of 1-benzylpyrazole-3-carboxylic acid.

Patent applications EP-A-576 357, EP-A-658 546 and WO-97/19063 describepyrazole derivatives having affinity for the cannabinoid receptors. Moreparticularly, patent application EP-A-656 354 claimsN-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamideand its pharmaceutically acceptable salts which have a very goodaffinity for the cannabinoid CB₁ receptors. Patent application EP-A-868420 describes pyrazole-3-carboxamide derivatives substituted at the1-position of pyrazole by a variously substituted benzyl group.

International patent application WO-96/09304 describes compoundsinhibiting cyclooxygenase, more specifically cyclooxygenase-2. Thesecompounds, which are useful in the treatment of inflammation andinflammatory diseases, correspond to the formula:

in which:

A, B, R_(a), R_(b), R_(d) have different meanings.

Novel tricyclic derivatives of 1-benzylpyrazole-3-carboxylic acid havenow been found which possess a very good affinity for the cannabinoidCB₂ receptors and which are useful in the therapeutic fields wherecannabis is known to be involved.

Δ⁹-THC is the main active constituent extracted from Cannabis sativa(Tuner, 1985; In Marijuana 84, Ed. Harvey, D Y, IRL Press, Oxford).

The effects of the cannabinoids are due to an interaction with specificreceptors of high affinity which are present at the central level(Devane et al., Mol. Pharmacol., 1988, 34, 605-613) and peripheral level(Nye et al., Pharmacol. and Experimental Ther., 1985, 234, 784-791;Kaminski et al., 1992, Mol. Pharmacol., 42, 736-742; Munro et al.,Nature, 1993, 365, 61-65).

The characterization of the receptors has been made possible by thedevelopment of synthetic ligands for the cannabinoid receptors such asthe agonists WIN 55212-2 (J. Pharmacol. Exp. Ther., 1993, 264,1352-1363) or CP 55,940 (J. Pharmacol. Exp. Ther., 1988, 247,1046-1051).

The subject of the present invention is compounds of formula:

in which:

-   X— represents a group —(CH₂)_(n)—;-   n is equal to 1 or 2;-   g₂, g₃, g₄, g₅, w₂, w₃, w₄, w₅, w₆ are identical or different and    each independently represent hydrogen, a halogen, a trifluoromethyl,    a (C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a (C₁-C₄)alkylthio, a nitro;-   R₁ represents a nonaromatic C₃-C₁₅ carbocyclic radical which is    unsubstituted or substituted one or several times with a    (C₁-C₄)alkyl;    as well as their salts and their solvates.

The expression alkyl is understood to mean straight or branched alkyls.The methyl, ethyl, propyl, isopropyl groups are preferred.

The expression nonaromatic C₃-C₁₅ carbocyclic radical is understood tomean a condensed or bridged, saturated, mono- or polycyclic radical.These radicals comprise in particular the following radicals:

-   cyclopentyl, cyclohexyl, adamantyl, bicyclo[3.2.1]octyl, as well as    1,3,3-trimethylbicyclo[2.2.1]heptyl or fenchyl,    7,7-dimethylbicyclo[4.1.0]hep-3-yl.

The expression halogen is understood to mean a chlorine, bromine,fluorine or iodine atom.

The possible salts of the compounds of formula (I) comprise thepharmaceutically acceptable acid addition salts such as thehydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, methanesulfonate, methyl sulfate, maleate, oxalate, fumarate,naphthalenesulfonate, glyconate, gluconate, citrate, isethionate,para-toluenesulfonate, methylenesulfonate, benzenesulfonate orsuccinate.

The subject of the present invention is most particularly compounds offormula:

in which:

-   X— represents a group —(CH₂)_(n)—;-   n is equal to 1 or 2;-   g₂, g₃, g₄, g₅, w₂, w₃, w₄, w₅, w₆ are identical or different and    each independently represent hydrogen, a halogen, a trifluoromethyl,    a (C₁-C₃)alkyl, a (C₁-C₃)alkoxy, a (C₁-C₃)alkylthio, a nitro;-   R₁ represents a nonaromatic C₃-C₁₅ carbocyclic radical which is    unsubstituted or substituted one or several times with a    (C₁-C₄)alkyl;    as well as their salts and their solvates.

Among the compounds of formula (I), those in which g₂, g₅, w₅, w₆represent hydrogen and g₃, g₄, w₂, w₃ and w₄ have one of the valuesdefined above for the compounds of formula (I) except hydrogen arepreferred.

More particularly, the compounds of formula (I) are preferred in whichw₂, w₃ and w₄ represent chlorine or a methyl and g₃ and g₄ representschlorine, bromine or a methyl, the other substituents w and g beinghydrogen.

The compounds of formula (I) are also preferred in which R₁ represents acarbocyclic radical chosen from: 1,3,3-trimethylbicyclo[2.2.1]hept-2-yl,bicyclo[3.2.1]oct-3-yl, 7,7-dimethylbicyclo[4.1.0]hept-3-yl.

Among the compounds of formula (I) those in which —X— represents a group—CH₂—CH₂—, and those in which —X— represents a group —CH₂— can bedistinguished. The compounds of formula (I) in which —X— represents—CH₂— are preferred.

In the description, the following abbreviations are used:

ether: diethyl ether

iso ether: diisopropyl ether

EtOH: ethanol

MeOH: methanol

DCM: dichloromethane

AcOEt: ethyl acetate

LiHMDS: lithium salt of hexamethyldisilazane

(CO₂Et)₂: ethyl oxalate

PTSA: para-toluenesulfonic acid

PPA: polyphosphoric acid

DIBAL: diisobutylaluminum hydride

AcOH: acetic acid

RT: room temperature

m.p.: melting point

b.p.: boiling point

p: pressure

NMR: nuclear magnetic resonance. The NMR spectra are recorded at 200 MHzin DMSO d6

s: singlet; d: doublet; t: triplet; m: unresolved complex or multiplex.

The subject of the present invention is also a method for preparing acompound according to the invention, its salts and its solvates. Thismethod is characterized in that a functional derivative of an acid offormula:

in which —X— and g₂, g₃, g₄, g₅, w₂, w₃, w₄, w₅, w₆ are as defined abovefor (I), is treated with a compound of formula NH₂R₁ (III), in which R₁is as defined above for (I).

The reaction is carried out in a basic medium, for example in thepresence of triethylamine in a solvent such as dichloromethane ortetrahydrofuran.

As a functional derivative of the acid (II), it is possible to use theacid chloride, the anhydride, a mixed anhydride, a C₁-C₄ alkyl ester inwhich the alkyl is straight or branched, an activated ester, for examplethe p-nitrophenyl ester, or the free acid which is opportunelyactivated, for example, with N,N-dicyclohexylcarbodiimide or withbenzotriazol-N-oxotris(dimethylamino)phosphonium hexafluorophosphate(BOP).

Thus, by the method according to the invention, it is possible to reactthe acid chloride of formula (II) obtained by reacting thionyl chloridewith the acid of formula (II) in an inert solvent such as benzene ortoluene or a chlorinated solvent (dichloromethane, dichloroethane,chloroform for example), an ether (tetrahydrofuran, dioxane for example)or an amide (N,N-dimethylformamide for example) under an inertatmosphere, at a temperature of between 0° C. and the reflux temperatureof the solvent.

A variant to the procedure consists in preparing the mixed anhydride ofthe acid of formula (II) by reacting ethyl chloroformate with the acidof formula (II), in the presence of a base such as triethylamine.

The starting acid (II) is novel and constitutes another aspect of thepresent invention, its functional derivatives are also novel, inparticular its acid chloride and its C₁-C₄ alkyl ester.

The acid of formula (II) may be obtained according to the reactionscheme below:

The acid of formula (II) may also be prepared by the action of aderivative of the benzylhydrazine of formula (IX) on a compound offormula (V), according to SCHEME 2 below.

Using the method according to SCHEME 1, by the action of the benzylhalide derivative of formula (VII) on the compound of formula (VI),there may also be formed a position isomer of the compound of formula(VIII), namely a compound of formula

Likewise, using the method according to SCHEME 2, by the action of thebenzylhydrazine derivative of formula (IX) in which w₂ to w₆ are asdefined above for (I), there may also be formed a position isomer of thecompound of formula (VIII), namely a compound of formula (XI).

To obtain the acid of formula (II), it is possible to either separatethe 2 isomers of formula (VIII) and (XI), or to carry out the hydrolysisof the mixture of the isomers (VIII) and (XI) in order to prepare amixture of the acid of formula (II) and of its isomer of formula:

The separation of the isomers is carried out by conventional methods,for example by chromatography or by crystallization.

The compounds of formula (IV) are known or prepared by known methods.For example, the tetralones of formula (IV) in which —X— represents—CH₂—CH₂— are known or prepared by known methods as described inSynthetic Communications, 1991, 21, 981-987.

The lithium salt of formula (V) is prepared by the action of the lithiumsalt of hexamethyldisilazane and then of ethyl oxalate.

By the action of hydrazine hydrate, and then heating in the presence ofacetic acid or in the presence of para-toluenesulfonic acid in toluene,the compound of formula (VI) is prepared. The compound of formula (VI)is then treated with a strong base such as sodium hydride or sodiumamide in a solvent and then a benzyl halide of formula (VII) in whichHal represents a halogen, preferably chlorine or bromine, and w₂-w₆ areas defined above for (I) is caused to act. A saponification is thencarried out according to conventional methods, for example in thepresence of potassium hydroxide or lithium hydroxide in methanol, inorder to obtain the expected acid of formula (II).

The benzyl halides of formula (VII) are known or prepared by knownmethods.

In general, the compounds of formula (VII) in which Hal represents abromine atom may be prepared by the action of N-bromosuccinimide on thecorresponding derivatives of methylbenzene in the presence of dibenzoylperoxide. It is also possible to prepare a benzyl bromide from acorresponding benzyl alcohol by the action of hydrobromic acid insolution in water or in acetic acid. It is also possible to use theaction of phosphorus tribromide on a corresponding benzyl alcohol inorder to prepare a compound of formula (VII) in which Hal represents abromine atom.

The compounds of formula (VII) in which Hal represents an iodine atommay be prepared by the action of sodium iodide on a compound of formula(VII) in which Hal represents a chlorine atom in a solvent such asacetone or butan-2-one.

The compounds of formula (VII) in which Hal represents a chlorine atommay be prepared by the action of thionyl chloride on a correspondingbenzyl alcohol.

The starting amine-containing derivatives of formula (III) are known orprepared by known methods, in particular those described in EP-A-868420. (1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ylamine is preparedaccording to J. Am. Chem. Soc., 1951, 73, 3360 or according to J. Med.Chem., 1991, 34, 1003-1010. Bicyclo[3.2.1]octan-3-ylamine is preparedaccording to H. Maskill et al., J. Chem. Soc. Perkin Trans II, 1984,1369.

The compound of formula (I) obtained by the method according to theinvention is isolated in the form of a free base or salt or solvate,according to conventional techniques.

The compound of formula (I) may be isolated in the form of one of itssalts, for example the hydrochloride or oxalate; in this case, the freebase may be prepared by neutralizing said salt with an inorganic ororganic base, such as sodium or ammonium hydroxide, triethylamine or analkali metal carbonate or bicarbonate such as sodium or potassiumcarbonate or bicarbonate, and converted to another salt such asmethanesulfonate, fumarate or 2-naphthalenesulfonate.

When the compound of formula (I) is obtained in the form of a free base,the salification is carried out by treating with the chosen acid in anorganic solvent. By treating the free base, dissolved for example in anether such as diethyl ether or in acetone, with a solution of the acidin the same solvent, the corresponding salt is obtained which isisolated according to conventional techniques.

The compounds of formula (I) possess a very good affinity in vitro forthe cannabinoid CB₂ receptors, under the experimental conditionsdescribed by Devane et al., Mol. Pharmacol., 1988, 34, 605-613.

More particularly, the compounds of the present invention, as they areor in the form of one of their pharmaceutically acceptable salts, arepotent and selective antagonists of the cannabinoid CB₂ receptors,having a Ki of less than 5×10⁻⁷ M. They are at least 10 times moreactive on the CB₂ receptors than on the CB₁ receptors and are active bythe oral route.

Moreover, their antagonist nature has been demonstrated by the resultsin the models for inhibition of adenylate-cyclase induced by forskolinas described in M. Rinaldi-Carmona et al., J. Pharm. Exp. Therap., 1998,284, 644-650.

The toxicity of the compounds (I) is compatible with their use as amedicament.

According to another of its aspects, the present invention relates tothe use of the compounds of formula (I), or of one of theirpharmaceutically acceptable salts and solvates, for the preparation ofmedicaments intended for treating diseases involving the cannabinoid CB₂receptors.

The diseases for the treatment of which the compounds (I) and,optionally, their pharmaceutically acceptable salts may be used arepathologies involving the cells of the immune system or immunedisorders, for example AIDS, autoimmune diseases, diseases related toorgan transplants, infectious diseases, allergic diseases, diseases ofthe gastrointestinal system, for example Crohn's disease, inflammatorybowel disease; more particularly there may be mentioned the followingautoimmune diseases: systemic lupus erythematosis, diseases of theconnective tissue or collagen disease, Sjögren's syndrome, ankylosingspondylitis, reactive arthritis, rheumatoid arthritis, undifferentiatedspondylarthritis, Behcet's disease, autoimmune hemolytic anemia,multiple sclerosis, psoriasis. The allergic diseases to be treated maybe of the immediate or delayed hypersensitivity type, asthma forexample. Likewise, the compounds and their possible pharmaceuticallyacceptable salts may be used for treating vasculitis, parasiticinfections, viral infections, bacterial infections, amylosis, diseasesaffecting the lines of the lymphohematopoietic system.

The compounds according to the invention are also useful asanti-inflammatory agent, as anti-arthritic agent, as analgesic, in thetreatment and prevention of vertigo, emesis and nausea, in particularnausea induced by anticancer agents, in the treatment of diabetes and inthe treatment of ocular diseases, for example ocular hypertension orglaucoma.

Furthermore, the compounds according to the invention may be useful inthe treatment of certain diseases of the central or peripheral nervoussystem, for example epilepsy, psychotic disorders, Alzheimer's disease,Parkinson's disease, Tourette's disease, Huntington chorea, as well asin the treatment of certain cancers.

Thus, according to another of its aspects, the present invention relatesto a method for treating the above diseases which consists inadministering to a patient requiring it an effective quantity of acompound of formula (I) or of one of its pharmaceutically acceptablesalts.

The compounds (I) according to the invention, as they are or inradio-labeled form may moreover be used as pharmacological tools inhumans or in animals, for the detection and labeling of peripheralcannabinoid CB₂ receptors. That constitutes a subsequent aspect of thepresent invention.

The compounds according to the invention are generally administered as adosage unit.

Said dosage units are preferably formulated in pharmaceuticalcompositions in which the active ingredient is mixed with apharmaceutical excipient.

Thus, according to another of its aspects, the present invention relatesto pharmaceutical compositions containing, as active ingredient, acompound of formula (I), one of its pharmaceutically acceptable salts orone of their solvates. The above compounds of formula (I) and theirpharmaceutically acceptable salts or solvates may be used at daily dosesof 0.01 to 100 mg per kg of body weight of the mammal to be treated,preferably at daily doses of 0.1 to 50 mg/kg. In human beings, the dosemay preferably vary from 0.5 to 4 000 mg per day, more particularly from2 to 1 000 mg per day according to the age of the subject to be treatedor the type of treatment, namely prophylactic or curative. Althoughthese doses are examples of average situations, there may be specificcases where higher or lower doses are appropriate, such doses alsobelong to the invention. According to the usual practice, the dosageappropriate for each patient is determined by the doctor according tothe mode of administration, the weight and the response of said patient.

In the pharmaceutical compositions of the present invention for oral,sublingual, inhaled, subcutaneous, intramuscular, intravenous,transdermal, local or rectal administration, the active ingredient maybe administered in unit form for administration, as a mixture withconventional pharmaceutical carriers, to animals and to human beings.The appropriate unit forms for administration comprise the forms foradministration by the oral route such as tablets, gelatin capsules,powders, granules and oral solutions or suspensions, the forms forsublingual and buccal administration, aerosols, the forms for topicaladministration, implants, the forms for subcutaneous, intramuscular,intravenous, intranasal or intraocular administration and the forms forrectal administration.

In the pharmaceutical compositions of the present invention, the activeingredient is generally formulated in the form of dosage unitscontaining from 0.1 to 1 000 mg, advantageously from 0.5 to 500 mg,preferably from 1 to 200 mg of said active ingredient per dosage unitfor daily administrations.

When a solid composition in tablet form is prepared, it is possible toadd to the micronized or nonmicronized active ingredient a wetting agentsuch as sodium lauryl sulfate and the whole is mixed with apharmaceutical vehicle such as silica, gelatin, starch, lactose,magnesium stearate, talc, gum arabic or the like. It is possible to coatthe tablets with sucrose, with various polymers or with otherappropriate materials or alternatively to treat them such that they havea prolonged or delayed activity and they continuously release apredetermined quantity of active ingredient.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with a diluent such as a glycol or a glycerol esterand by incorporating the mixture obtained into soft or hard gelatincapsules.

A preparation in syrup or elixir form may contain the active ingredienttogether with a sweetener, preferably a calorie-free sweetener,methylparaben and propylparaben as antiseptics, as well as a flavoringagent and an appropriate colorant.

The water-dispersible powders or granules may contain the activeingredient as a mixture with dispersing agents, wetting agents orsuspending agents, such as polyvinylpyrrolidone, as well as withsweeteners or flavor correctors.

For rectal administration, suppositories are used which are preparedwith binders melting at the rectal temperature, for example cocoa butteror polyethylene glycols.

For parenteral, intranasal or intraocular administration, aqueoussuspensions, isotonic saline solutions or sterile and injectiblesolutions which contain pharmacologically compatible dispersing agentsand/or solubilizing agents, for example propylene glycol or polyethyleneglycol, are used.

Thus, to prepare an aqueous solution which is injectible by theintravenous route, it is possible to use a cosolvent such as, forexample, an alcohol such as ethanol or a glycol such as polyethyleneglycol or propylene glycol, and a hydrophilic surfactant such as Tween®80. To prepare an oily solution which is injectible by the intramuscularroute, the active ingredient may be solubilized with a triglyceride or aglycerol ester.

For local administration, creams, ointments or gels may be used.

For transdermal administration, patches may be used in multilaminateform or in a form containing reservoirs in which the active ingredientmay be in alcoholic solution.

For administration by inhalation, an aerosol is used containing, forexample, sorbitan trioleate or oleic acid as well astrichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethaneor any other biologically compatible propellant gas; it is also possibleto use a system containing the active ingredient alone or combined withan excipient, in powdered form.

The active ingredient may be generally formulated in the form ofmicrocapsules or microspheres, optionally with one or more carriers oradditives.

The active ingredient may also be provided in the form of a complex witha cyclodextrin, for example α-, β- or γ-cyclodextrin,2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.

Among the prolonged release forms which are useful in the case ofchronic treatments, implants may be used. These may be prepared in theform of an oily suspension or in the form of a suspensions ofmicrospheres in an isotonic medium.

PREPARATIONS Preparation 1.1 Ethyl ester of6-chloro-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acid

(VI): X=CH₂, g₄=Cl

A) Ethyl ester of the lithium salt of(5-chloro-1-oxidoindan-2-yl)oxoacetic acid

A solution of 4.42 g of LiHMDS is prepared at −60° C. in 140 ml of Et₂Oand a solution of 4.0 g of 5-chloroindan-1-one in 10 ml of Et₂O is addeddropwise. The mixture is kept stirring for 30 minutes, while allowingthe temperature to rise to −30° C. and then 3.6 ml of ethyl oxalate areadded. After stirring for 18 hours at RT, the yellow precipitateobtained is filtered, washed with water and then dried under vacuum.6.42 g of the expected compound are obtained.

B) Ethyl ester of6-chloro-1,4-dihydroindeno[1,2-c]-pyrazole-3-carboxylic acid

0.56 ml of hydrazine hydrate is added to a solution, cooled on an icebath, containing 3 g of the compound obtained in the preceding step in20 ml of acetic acid. The mixture is heated under reflux for 18 hoursand then the reaction mixture is poured into 100 ml of ice-cold water.The mixture is filtered, washed with water and then dried under vacuumto give 2.62 g of the expected compound, m.p.=190° C.

NMR: 1.25 ppm: t: 3H; 3.70 ppm: s: 2H; 4.25 ppm: q: 2H; 7.25-7.65 ppm:m: 3H; 13.80 ppm: s: 1H.

Preparation 1.2 Ethyl ester of6-chloro-7-methyl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acid

(VI): X=CH₂, g₃=CH₃, g₄=Cl

A) 3-Chloro-1-(4-chloro-3-methylphenyl)propan-1-one

23.43 ml of 2-chlorotoluene and 26.6 g of 3-chloropropionyl chloride aremixed in 25 ml of carbon sulfide and 32 g of AlCl₃ in 125 ml of carbonsulfide are added over 45 minutes. After stirring for 3 hours at RT, thesolvent is evaporated and then 1 liter of water is added. The reactionmedium is extracted with ether and then with benzene, and then theorganic phase is washed with a saturated Na₂CO₃ solution and then withwater. It is dried over Na₂SO₄ and then the residue is chromatographedon a silica column, eluting with an AcOEt/cyclohexane (5/95; v/v)mixture. 27.25 g of the expected compound are obtained.

NMR: 2.4 ppm: s: 3H; 3.6 ppm: t: 2H; 3.9 ppm: t: 2H; 7.6 ppm: m: 1H; 7.8ppm: m: 1H; 8 ppm: m: 1H.

B) 5-Chloro-6-methylindanone

250 ml of concentrated H₂SO₄ are slowly added, with vigorous stirring,to 30.67 g of the compound prepared in the preceding step. The mixtureis heated at 90° C. for one hour and then poured over ice. The mixtureis extracted with ether and then the organic phase is dried over Na₂SO₄and evaporated to dryness. The residue is chromatographed on silica,eluting with an AcOEt/cyclohexane (5/95; v/v) mixture. 1.8 g of theexpected compound are obtained.

NMR: 2.3 ppm: s: 3H; 2.5-2.6 ppm: m: 2H; 2.9-3 ppm: m: 2H; 7.5 ppm: s:1H; 7.6 ppm: s: 1H.

C) Ethyl ester of6-chloro-7-methyl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acid

The procedure is then carried out as described in PREPARATION 1.1 insteps A and B in order to prepare the expected compound.

NMR: 1.2 ppm: t: 3H; 2.3 ppm: s: 3H; 3.6 ppm: s: 2H; 4.2 ppm: q: 2H; 7.4ppm: s: 1H; 7.5 ppm: s: 1H; 13.7 ppm: s: 1H.

By carrying out the procedure according to PREPARATION 1.1, thecompounds described in TABLE 1 are prepared.

TABLE 1 (VI)

Preparation X g₂ g₃ g₄ g₅ m.p. ° C. 1.3 CH₂ H H Br H NMR: 1.4 ppm: t:3H; 3.8 ppm: s: 2H; 4.4 ppm: q: 2H; 7.6-7.8 ppm: m: 2H; 7.9 ppm: s: 1H;13.9 ppm: s: 1H 1.4 CH₂—CH₂ H H Cl H 170° C.

Preparation 2.11-(2,4-Dichlorobenzyl)-6-chloro-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylicacid

II, X=CH₂; g₄=w₂=w₄=Cl

A) Ethyl ester of1-(2,4-dichlorobenzyl)-6-chloro-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylicacid

A suspension of 2.48 g of the compound obtained in PREPARATION 1 isprepared in 50 ml of toluene and 0.45 g of 60% sodium hydride in oil isadded in 3 portions, and then the mixture is heated at 65° C. for 1hour. After returning to RT, 1.38 ml of 2,4-dichlorobenzyl chloride areadded and then the mixture is heated under reflux for 44 hours. 100 mlof a saturated NH₄Cl solution is added, the medium is filtered and thenthe organic phase is evaporated under vacuum and the residue is mixedwith the precipitate and triturated in AcOEt. The mixture is filtered,washed with AcOEt and then dried under vacuum to give 3.00 g of theexpected compound, m.p.=168° C.

B)1-(2,4-Dichlorobenzyl)-6-chloro-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylicacid

2.97 g of the compound obtained in the preceding step are placed in 60ml of MeOH, 1.01 g of KOH in 10 ml of water are added and then themixture is heated under reflux for 4 hours. The reaction medium is thenpoured into a mixture containing 200 ml of ice-cold water and 20 ml of10% HCl. The mixture is filtered, washed with water and then dried undervacuum to give 2.50 g of the expected compound, m.p.>260° C.

NMR: 3.75 ppm: s: 2H; 5.80 ppm: s: 2H; 7.05 ppm: d: 1H; 7.30-7.80 ppm:m: 5H.

By carrying out the procedure according to PREPARATION 2.1, thecompounds described in the TABLE below are prepared.

TABLE 2 (II)

NMR/m.p. Preparation X g₃ g₄ w₂ w₃ w₄ ° C. 2.2 —CH₂— H Cl H Cl CH₃ 2.2ppm: s: 3H; 3.8 ppm: s: 2H; 5.7 ppm: s: 2H; 7-7.8 ppm: m: 6H; 12.4- 13ppm: m: 1H 2.3 CH₂ H Br H H CH₃ 2.2 ppm: s: 3H; 3.6 ppm: s: 2H; 5.5 ppm:s: 2H; 7 ppm: s: 4H; 7.4 ppm: s: 2H; 7.7 ppm: s: 1H 2.4 CH₂ H Br H Cl Cl3.7 ppm: s: 2H; 5.7 ppm: s: 2H 7.2-7.3 ppm: dd: 1H; 7.5- 7.7 ppm: m: 4H;7.8 ppm: s: 1H 2.5 CH₂ H Br Cl H Cl 3.7 ppm: s: 2H; 4-5 ppm: m: 1H; 5.6ppm: s: 2H; 6.9 ppm: d: 1H; 7.2- 7.4 ppm: dd: 1H; 7.7 ppm: s: 1H; 7.8ppm: s: 1H 2.6 CH₂ CH₃ Cl H Cl Cl 2.4 ppm: s: 3H; 3.6 ppm: s: 2H; 4.2-4.4 ppm: m: 1H; 5.8 ppm: s: 2H; 7.3 ppm: d: 1H; 7.7 ppm: t: 1H; 7.9 ppm:d: 1H 2.7 CH₂—CH₂ H Cl Cl H Cl 2.90 ppm: s: 2H; 5.70 ppm: s: 2H; 6.65ppm: d: 1H; 7.20- 7.70 ppm: m: 4H 2.8 CH₂ H Br H H Cl 276° C. 2.9 CH₂ HBr H H CF₃ 263° C. 2.10 CH₂—CH₂ H OMe H Cl Cl 221° C.

Preparation 3 7,7-Dimethylbicyclo[4.1.0]hept-3-ylamine, hydrochloride

A) 7,7-Dimethylbicyclo[4.1.0]heptan-3-one oxime 5 g of7,7-dimethylbicyclo[4.1.0]hept-3-one are dissolved in 25 ml of MeOH and18 ml of CHCl₃ and 3.77 g of hydroxylamine and 5.9 g of sodium acetatedissolved in 100 ml of water are added. The mixture is heated underreflux for 56 hours and then cooled. It is extracted with ether and thenthe ethereal phase is dried over Na₂SO₄ and evaporated to dryness. Theoil obtained (6.56 g) is used as it is in the next step.B) 7,7-Dimethylbicyclo[4.1.0]hept-3-ylamine, hydrochloride

6.5 g of the product obtained in the preceding step is dissolved in 150ml of EtOH and the mixture is placed in a hydrogen bomb. 3 ml of CHCL₃and 1.5 g of PtO₂ are added and then the mixture is left under an H₂atmosphere at a pressure of 7.8 bar for 72 hours. The mixture isfiltered on Celite®, evaporated to dryness, and then taken up in ether,drained and dried under vacuum. 3.37 g of the expected compound areobtained.

NMR: 0.95 ppm: s: 3H; 1.10 ppm: s: 3H; 1.50-2.30 ppm: m: 8H; 3.40-3.55ppm: m: 1H; 8.00 ppm: s: 2H.

EXAMPLE 1N-[(1S)-1,3,3-Trimethylbicyclo[2.2.1]hept-2-endo-yl-6-chloro-1-(2,4-dichlorobenzyl)-1,4-dihydroindeno[1,2-c]-pyrazole-3-carboxamide

I, X=CH₂; g₄=w₂=w₄=Cl;

A)1-(2,4-dichlorobenzyl)-6-chloro-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylicacid chloride

2.45 g of the compound obtained in PREPARATION 2.1 in 35 ml of tolueneand 1.36 ml of SOCl₂ are mixed and the mixture is heated under refluxfor 2 hours. The solvent is evaporated under vacuum and then the residueis taken up in 30 ml of toluene and evaporated to dryness (twice). 2.59g of the expected compound are obtained.

B)N-[(1S)-1,3,3-Trimethylbicyclo[2.2.1]hept-2-endo-yl-6-chloro-1-(2,4-dichlorobenzyl)-1,4-dihydro-indeno[1,2-c]pyrazole-3-carboxamide

A solution of 0.80 g of the compound obtained in the preceding step in20 ml of DCM is added dropwise over a solution, cooled to 0° C., of 0.37g of (1S)-endo-1,3,3-trimethylbicyclo[2.2.1]hept-2-ylamine and 0.55 mlof NEt₃ in 20 ml of DCM. The mixture is kept stirring at RT for 16 hoursand then the reaction medium is poured over 100 ml of ice-cold water.The mixture is extracted with DCM, the solvent is evaporated, dried overMgSO₄ and then the residue is chromatographed on silica, eluting with anAcOEt/toluene (1/9; v/v) mixture. The compound obtained crystallizesfrom isopropyl ether. 0.46 g is obtained, m.p.=157° C.

NMR: 0.75 ppm: s: 3H; 1.00-1.75 ppm: m: 13H; 3.65 ppm: d: 1H; 3.80 ppm:s: 2H; 5.80 ppm: s: 2H; 6.90-7.10 ppm: m: 2H; 7.35-7.45 ppm: m: 2H;7.55-7.70 ppm: m: 3H.

By carrying out the procedure according to EXAMPLE 1, the compoundsaccording to the invention described in the TABLE below are prepared,

TABLE 3 (I)

Examples X g₃ g₄ w₂ w₃ w₄ R₁ α_(D) m.p. 2 CH₂ H Cl Cl H Cl

197 3 CH₂ H Cl H Cl Cl

−6.9 (c = 1, MeOH) 158 4 CH₂ H Cl H Cl Cl

93 5 CH₂ H Cl H Cl CH₃

−9.6 (c = 1, MeOH) 78-83 6 CH₂ H Cl H Cl CH₃

74-78 7 CH₂ H Br H H CH₃

−14.2 (c = 1, EtOH) 78 8 CH₂ H Br H H CH₃

−18.3 (c = 1, EtOH) 105 9 CH₂ H Br H Cl Cl

−10.3 (c = 1, EtOH) 149 10 CH₂ H Br Cl H Cl

−7.2 (c = 1, EtOH) 92 11 CH₂ CH₃ Cl H Cl Cl

−7.3 (c = 1, EtOH) 100 12 CH₂ CH₃ Cl H Cl Cl

90 13 CH₂—CH₂ H Cl Cl H Cl

−1.2 (c = 1, EtOH) 97 14 CH₂—CH₂ H OMe H Cl Cl

172 15 CH₂—CH₂ H OMe H Cl Cl

−8.1 (c = 1; CHCl₃) 104 16 CH₂ H Br Cl H Cl

190 17 CH₂ H Br Cl H Cl

196 18 CH₂ H Br H H Cl

−8.8 (c = 1, MeOH) 82 19 CH₂ H Br H H Cl

181 20 CH₂ H Br H H CF₃

−5.9 (c = 1, MeOH) 85 21 CH₂ H Br H H CF₃

87

1. A compound of formula:

in which: X— represents a group —(CH₂)_(n)—; n is equal to 1 or 2; g₂,g₃, g₄, g₅, w₂, w₃, w₄, w₅, w₆ are identical or different and eachindependently represent hydrogen, a halogen, a trifluoromethyl, a(C₁-C₄)alkyl, a (C₁-C₄)alkoxy, a (C₁-C₄)alkylthio, a nitro; R₁represents a nonaromatic C₃-C₁₅ carbocyclic radical which isunsubstituted or substituted one or several times with a (C₁-C₄)alkyl;or a pharmaceutically acceptable salt or solvate thereof.
 2. Thecompound as claimed in claim 1, in which g₂, g₅, w₅, w₆ representhydrogen.
 3. The compound as claimed in claim 2, in which w₂, w₃ and w₄represent chlorine or a methyl and g₃ and g₄ represents chlorine,bromine or a methyl.
 4. The compound as claimed in claim 3 of formula(I), in which R₁ represents a carbocyclic radical chosen from:1,3,3-trimethylbicyclo[2.2.1]hept-2-yl, bicyclo[3.2.1]oct-3-yl,7,7-dimethylbicyclo[4.1.0]hept-3-yl.
 5. The compound as claimed in claim1 of formula (I), in which —X— represents —CH₂—.
 6. A method forpreparing a compound as claimed in claim 1 wherein a functionalderivative of an acid of formula:

in which —X— and g₂, g₃, g₄, g₅, w₂, w₃, w₄, w₅, w₆ are as defined inclaim 1 for (I), is treated with a compound of formula NH₂R₁ (III), inwhich R₁ is as defined in claim
 1. 7. A pharmaceutical compositioncontaining a compound as claimed in claim
 1. 8. The pharmaceuticalcomposition as claimed in claim 7, in dosage unit form.
 9. The compoundas claimed in claim 4 in which —X— represents —CH₂—.
 10. Apharmaceutical composition containing a compound as claimed in claim 2.11. A pharmaceutical composition containing a compound as claimed inclaim
 3. 12. A pharmaceutical composition containing a compound asclaimed in claim
 4. 13. A pharmaceutical composition containing acompound as claimed in claim
 5. 14. A pharmaceutical compositioncontaining a compound as claimed in claim 9.